The goal of this exploratory developmental proposal is to obtain initial data to support an R01 application that systematically examines the neurobiology of increased cortical excitability in human MDMA (Ecstasy) users. MDMA, a drug that has well-demonstrated serotonin (5-HT) neurotoxic effects in rodents and non-human primates, is widely used by young adults. Understanding the neural consequences of addictive drugs is of critical importance to NIDA's mission to reduce drug use and its negative effects. Our earlier research found that MDMA leads to probable increases in cortical excitability. Increased cortical excitability has profound implications for the brain, relating MDMA toxicity to seizure disorders, dementia, and psychiatric conditions. This putative MDMA-associated increase in cortical excitability correlates positively both with lifetime quantity of MDMA consumed and also with the duration of abstinence from MDMA. We now request funding via the Exploratory Developmental (R21) mechanism to explore the neural mechanism for these findings by: 1) by using transcranial magnetic stimulation (TMS) in visual and motor cortex to demonstrate MDMA users have increased cortical excitability and, 2) to use magnetic resonance spectroscopy (MRS) to determine if MDMA users have increased cortical glutamate (Glu) and decreased cortical gamma-amino- butyric acid (GABA). We will link functional magnetic resonance imaging (fMRI), TMS, and MRS results to demonstrate whether the increased task-evoked activation previously demonstrated with fMRI is correlated with increased cortical excitability and changes in cortical Glu and GABA. We will also explore the link between these measures and depression and anxiety. Based upon the role of 5-HT in brain neurophysiology and upon the specific mechanism of MDMA toxicity, we have developed a translational neuroscience model to frame and interpret the proposed findings. We hypothesize that MDMA-induced loss of cortical 5-HT axons leads to a net loss of 5-HT inhibition that will be associated with increased Glu and GABA concentrations. Findings from this exploratory application will be used to support an R01 application to systematically examine the role of MDMA in producing altered cortical neurophysiology.